Glycogen storage disease type Ia (GSD-Ia or von Gierke disease, MIM232200) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), an enzyme that is expressed primarily in the liver, kidney, and intestine (Chou et al. Nat Rev Endocrinol 6:676-688, 2010). C6Pase-α, encoded by the G6PC gene, is a hydrophobic protein anchored in the endoplasmic reticulum (ER) by nine transmembrane helices (Chou et al., Nat Rev Endocrinol 6:676-688, 2010). This enzyme catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the terminal step of glycogenolysis and gluconeogenesis. Patients affected by GSD-Ia are unable to maintain glucose homeostasis and present with fasting hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia (Chou et al., Nat Rev Endocrinol 6:676-688, 2010).
There is currently no cure for GSD-Ia. Hypoglycemia can be managed using dietary therapies (Greene et al. N Engl Med 294:423-425, 1976; Chen et al. N Engl Med 310:171-175, 1984) that enable patients to attain near normal growth and pubertal development. However, the longer term clinical complications, and their underlying pathological processes, remain uncorrected. One of the most significant chronic risks is hepatocellular adenoma (HCA), that develops in 70-80% of GSD-I patients over 25 years old (Chou et al., Nat Rev Endocrinol 6:676-688, 2010; Labrune et al., J Pediatr Gastroenterol Nutr 24:276-279 1997; Rake et al., Eur J Pediatr 161(Suppl. 1):S20-S34, 2002). HCAs in GSD-Ia patients are small, multiple, and nonencapsulated, with complications including local compression and intratumoral hemorrhage. In 10% of GSD-Ia patients, HCAs undergo malignant transformation to hepatocellutar carcinoma (HCC) (Chou et al., Nat Rev Endocrinol 6:676-688, 2010; Rake et al., Eur J Pediatr 161(Suppl 1):S20-S34, 2002; Franco et al., J Inherit Metab Dis 28:153-162, 2005).
Gene therapy studies using recombinant adeno-associated virus (AAV) carrying G6Pase-α have been performed in animal models of GSD-Ia; these studies have demonstrated efficacy in the absence of toxicity (reviewed in Chou and Mansfield, Expert Opin Biol Ther 11:1011-1024, 2011). Previous studies using the mouse model of GSD-Ia have shown that recombinant AAV expressing G6Pase-α directed by the CBA promoter/CMV enhancer (Ghosh et al., Gene Ther 13:321-329, 2006), the canine G6PC promoter (Koeberl al., Gene Ther 13:1281-1289, 2006), or the human G6PC promoter at nucleotides −298 to +128 of the G6PC 5′ flanking region (Koeberl et al., Mol Ther 16:665-672, 2008) deliver the G6Pase-α transgene to the liver and achieve extended correction of this disorder. However, while these studies have shown promise, none have been capable of completely correcting hepatic G6Pase-α deficiency.